Drug delivery and diagnostic systems based on target-specific polymeric vehicles have become of interest in recent years.
Targeted drug delivery, i.e. delivery of a therapeutic drug to a specific tissue or diseased cell is associated with a number of advantages. With a targeted approach, systemic toxicity can be reduced or avoided; drug dosing may also be reduced. The problem of poor solubility, of an otherwise efficacious drug candidate may be also overcome. The use of polymeric delivery systems is also advantageous in that these may be retained and circulated for a longer period of time, thus bypassing the typically faster clearance of the active agent from the body. In respect of targeted delivery of diagnostic agents, an improved localization of an imaging agent to a specific organ or tissue type can bring about a more assured diagnosis.
An example of a polymeric drug delivery system is those that are based on PEG (polyethylene glycol). PEG-polymer-conjugated small molecular pharmaceuticals or bio-pharmaceuticals have been developed and indeed, many of these conjugates have been found to have improved properties such as increased drug solubility, half-life extension, low cytotoxicity and immunogenicity. Although PEG, to certain degree remains a gold-standard in polymer-based biomedical applications, there are however disadvantages and limitations in respect of this type of polymer. For example, hypersensitivity and the formation of PEG antibodies have been observed in several instances. In particular, PEG, has somewhat limited functionality available for modification and for orthogonal functionalization.
Other polymer systems have also been investigated such as those based on poly-2-oxazoline (also abbreviated as PDX). This type of polymer are useful in biomedical applications as these also have generally been found to be biocompatible, and moreover, tend to have immunological ‘stealth’ i.e. non-specific binding properties so that recognition by the immune defence system and fast clearance is avoided.
Amphiphilic polymer systems comprising poly-2-oxazoline as a structural element have been developed.
For example, US2008/0305149 describes the preparation amphiphilic triblock segmented copolymers comprising poly-2-methyloxazoline and polydimethylsiloxane segments (i.e. poly(2-methyloxazoline)-block-poly(dimethylsiloxane)-block-poly(2-methyloxazoline) triblock polymers, or abbreviated as PMOXA-PDMS-PMOXA), and their use in making vesicles with a mucoadhesive outer surface. It is described that these vesicles may be used for delivery of an active agent, which are encapsulated within the vesicle. Such vesicles however cannot be readily be modified for targeted drug delivery. The amphiphilic polymers used to prepare the vesicles are limited in terms of options for further functionalization.
Broz et al (J. Control. Release 2005 (102) 475-488) describe nanocontainers based also on PMOXA-PDMS-PMOXA amphiphilic polymers. In this instance, the amphiphilic polymers are terminally functionalized with biotin. The biotin ligand is used as a means for linking the nanocontainer, with streptavidin as a linchpin, to a receptor specific ligand, i.e. a polyguanylic acid (polyG) oligonucleotide that is also biotinylated. Although the biotin-streptavidin bond is strong, it is however not irreversible; this kind of linkage is also not the most suitable for in vivo use.
It is therefore an object of the present invention to introduce novel poly-2-oxazoline amphiphilic polymers and copolymers, for use in the preparation of self-assembled particles, and which overcomes any of the limitations and disadvantages of the current polymer systems. A further object is to develop self-assembled particles which may be used for targeted delivery of a therapeutic agent or diagnostic agent.